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Brain Tumors: Molecular and Cell Biology for Target Therapy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 24907

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Special Issue Editors

Dr. Stefania Elena Navone

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Guest Editor

Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Interests: glioblastoma; brain tumor; angiogenesis; platelets; personalized medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Giovanni Marfia

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Guest Editor

1. Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
2. Aerospace Medicine Institute “A. Mosso”, Italian Air Force, 20138 Milan, Italy
Interests: central nervous system tumors; cerebrovascular pathology; degenerative spinal pathology; aerospace medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epidemiological data indicate that cancer incidence is rapidly growing. Inheritance, gender, geography, and exposure to electromagnetic radiations are among the etiological factors of brain tumors. Most malignant primary tumors of the adult brain originate from glial cells or glial cell precursors and are so-called gliomas. Malignant gliomas are highly invasive, neurologically destructive, and characterized by high tumor heterogeneity, uncontrolled proliferation, and resistance to therapies. Among these tumors, glioblastoma is the deadliest.

In 2016, the World Health Organization (WHO) provided new guidelines for cerebral neoplasm, introducing molecular markers in addition to the classic histopathological criteria.

This new approach integrates genotypic and phenotypic parameters, increasing the accuracy of the diagnostic procedure in order to facilitate the implementation of targeted treatments. Despite these new criteria, brain tumors still lack effective treatments. Currently available therapeutic options neglect the individuality of each patient’s disease and only temporarily influence tumor progression with a poor effect on overall survival, highlighting the great importance of the introduction of target treatments in neuro-oncology.

This Special Issue will highlight the importance of exploring brain tumors at cellular and molecular levels, to outline novel strategic approaches for brain tumor target therapy. With this issue, we aim to advance brain tumor cure, dissecting all aspects ranging from basic biology to translational medicine.

Dr. Stefania Navone
Dr. Giovanni Marfia
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

brain tumors
glioblastoma
molecular and cellular biology
target treatment
personalized medicine

Published Papers (7 papers)

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Research

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18 pages, 3590 KiB

Open AccessEditor’s ChoiceArticle

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

by Tsung-Han Hsieh, Muh-Lii Liang, Jia-Huei Zheng, Yu-Chen Lin, Yu-Chen Yang, Thanh-Hoa Vo, Jing-Ping Liou, Yun Yen and Chun-Han Chen

Cancers 2021, 13(23), 6117; https://doi.org/10.3390/cancers13236117 - 4 Dec 2021

Cited by 4 | Viewed by 2959

Abstract

Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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19 pages, 3932 KiB

Open AccessArticle

Gasdermin D Is a Novel Prognostic Biomarker and Relates to TMZ Response in Glioblastoma

by Junhui Liu, Lun Gao, Xiaonan Zhu, Rongxin Geng, Xiang Tao, Haitao Xu and Zhibiao Chen

Cancers 2021, 13(22), 5620; https://doi.org/10.3390/cancers13225620 - 10 Nov 2021

Cited by 13 | Viewed by 2670

Abstract

The gasdermin (GSDM) family act as executioners during pyroptosis. However, its expression and biological role in glioma remain to be determined. This study carried out gene expression from six public datasets. Westerns blots and immunohistochemistry (IHC) staining were employed to examine GSDM expression in glioma in an in-house cohort. Kaplan–Meier and Cox regression analyses were performed to evaluate the prognostic role of GSDMs in glioma. Association between gene expression and immune infiltration was assessed by IHC and immunofluorescence (IF) staining of tissue sections. TMZ-induced pyroptosis was assessed by observation of morphological changes, WB and ELISA detection. Only GSDMD expression was upregulated in glioma compared with nontumor brain tissues both in the public datasets and in-house cohort. High GSDMD expression was significantly associated with WHO grade IV, IDH 1/2 wild-type and mesenchymal subtypes. Besides, high GSDMD expression was associated with shorter overall survival and could be used as an independent risk factor for poor outcomes in LGG and GBM. GO enrichment analysis and IHC validation revealed that GSDMD expression might participate in regulating macrophage infiltration and polarization. TMZ treatment induced the pyroptosis in GBM cells and GSDMD expression increased with after treating with TMZ in a time-dependent manner. Moreover, knocking down GSDMD obviously decreased IL-1β expression and reduced TMZ-induced pyroptosis in in vitro. GSDMD was a novel prognostic biomarker, as well as TMZ-treatment response marker in glioma. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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20 pages, 7768 KiB

Open AccessArticle

Impairment of Autophagic Flux Participates in the Antitumor Effects of TAT-Cx43_266-283 in Glioblastoma Stem Cells

by Sara G. Pelaz, Claudia Ollauri-Ibáñez, Concepción Lillo and Arantxa Tabernero

Cancers 2021, 13(17), 4262; https://doi.org/10.3390/cancers13174262 - 24 Aug 2021

Cited by 4 | Viewed by 2326

Abstract

Autophagy is a physiological process by which various damaged or non-essential cytosolic components are recycled, contributing to cell survival under stress conditions. In cancer, autophagy can have antitumor or protumor effects depending on the developmental stage. Here, we use Western blotting, immunochemistry, and transmission electron microscopy to demonstrate that the antitumor peptide TAT-Cx43_266-283, a c-Src inhibitor, blocks autophagic flux in glioblastoma stem cells (GSCs) under basal and nutrient-deprived conditions. Upon nutrient deprivation, GSCs acquired a dormant-like phenotype that was disrupted by inhibition of autophagy with TAT-Cx43_266-283 or chloroquine (a classic autophagy inhibitor), leading to GSC death. Remarkably, dasatinib, a clinically available c-Src inhibitor, could not replicate TAT-Cx43_266-283 effect on dormant GSCs, revealing for the first time the possible involvement of pathways other than c-Src in TAT-Cx43_266-283 effect. TAT-Cx43_266-283 exerts an antitumor effect both in nutrient-complete and nutrient-deprived environments, which constitutes an advantage over chloroquine and dasatinib, whose effects depend on nutrient environment. Finally, our analysis of the levels of autophagy-related proteins in healthy and glioma donors suggests that autophagy is upregulated in glioblastoma, further supporting the interest in inhibiting this process in the most aggressive brain tumor and the potential use of TAT-Cx43_266-283 as a therapy for this type of cancer. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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Graphical abstract

15 pages, 3022 KiB

Open AccessArticle

Dynein Light Chain Protein Tctex1: A Novel Prognostic Marker and Molecular Mediator in Glioblastoma

by Claudia Alexandra Dumitru, Eileen Brouwer, Tamina Stelzer, Salvatore Nocerino, Sebastian Rading, Ludwig Wilkens, Ibrahim Erol Sandalcioglu and Meliha Karsak

Cancers 2021, 13(11), 2624; https://doi.org/10.3390/cancers13112624 - 27 May 2021

Cited by 5 | Viewed by 2376

Abstract

The purpose of this study was to determine the role of Tctex1 (DYNLT1, dynein light chain-1) in the pathophysiology of glioblastoma (GBM). To this end, we performed immunohistochemical analyses on tissues from GBM patients (n = 202). Tctex1 was additionally overexpressed in two different GBM cell lines, which were then evaluated in regard to their proliferative and invasive properties. We found that Tctex1 levels were significantly higher in GBM compared to healthy adjacent brain tissues. Furthermore, high Tctex1 expression was significantly associated with the short overall- (p = 0.002, log-rank) and progression-free (p = 0.028, log-rank) survival of GBM patients and was an independent predictor of poor overall survival in multivariate Cox-regression models. In vitro, Tctex1 promoted the metabolic activity, anchorage-independent growth and proliferation of GBM cells. This phenomenon was previously shown to occur via the phosphorylation of retinoblastoma protein (phospho-RB). Here, we found a direct and significant correlation between the levels of Tctex1 and phospho-RB (Ser807/801) in tissues from GBM patients (p = 0.007, Rho = 0.284, Spearman’s rank). Finally, Tctex1 enhanced the invasiveness of GBM cells and the release of pro-invasive matrix metalloprotease 2 (MMP2). These findings indicate that Tctex1 promotes GBM progression and therefore might be a useful therapeutic target in this type of cancer. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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18 pages, 4206 KiB

Open AccessArticle

Neoplastic Cells are the Major Source of MT-MMPs in IDH1-Mutant Glioma, Thus Enhancing Tumor-Cell Intrinsic Brain Infiltration

by Ina Thome, Raphael Lacle, Andreas Voß, Ginette Bortolussi, Georgios Pantazis, Ansgar Schmidt, Catharina Conrad, Ralf Jacob, Nina Timmesfeld, Jörg W. Bartsch and Axel Pagenstecher

Cancers 2020, 12(9), 2456; https://doi.org/10.3390/cancers12092456 - 29 Aug 2020

Cited by 6 | Viewed by 2362

Abstract

Tumor-cell infiltration is a major obstacle to successful therapy for brain tumors. Membrane-type matrix metalloproteinases (MT-MMPs), a metzincin subfamily of six proteases, are important mediators of infiltration. The cellular source of MT-MMPs and their role in glioma biology, however, remain controversial. Thus, we comprehensively analyzed the expression of MT-MMPs in primary brain tumors. All MT-MMPs were differentially expressed in primary brain tumors. In diffuse gliomas, MT-MMP1, -3, and -4 were predominantly expressed by IDH1^mutated tumor cells, while macrophages/microglia contributed significantly less to MT-MMP expression. For functional analyses, individual MT-MMPs were expressed in primary mouse p53^−/− astrocytes. Invasion and migration potential of MT-MMP-transduced astrocytes was determined via scratch, matrigel invasion, and novel organotypic porcine spinal slice migration (OPoSSM) and invasion assays. Overall, MT-MMP-transduced astrocytes showed enhanced migration compared to controls. MMP14 was the strongest mediator of migration in scratch assays. However, in the OPoSSM assays, the glycosylphosphatidylinositol (GPI)-anchored MT-MMPs MMP17 and MMP25, not MMP14, mediated the highest infiltration rates of astrocytes. Our data unequivocally demonstrate for the first time that glioma cells, not microglia, are the predominant producers of MT-MMPs in glioma and can act as potent mediators of tumor-cell infiltration into CNS tissue. These proteases are therefore promising targets for therapeutic interventions. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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Review

Jump to: Research

18 pages, 881 KiB

Open AccessReview

Targeting Cell Cycle Checkpoint Kinases to Overcome Intrinsic Radioresistance in Brain Tumor Cells

by Tijana Vlatkovic, Marlon R. Veldwijk, Frank A. Giordano and Carsten Herskind

Cancers 2022, 14(3), 701; https://doi.org/10.3390/cancers14030701 - 29 Jan 2022

Cited by 6 | Viewed by 3499

Abstract

Radiation therapy is an important part of the standard of care treatment of brain tumors. However, the efficacy of radiation therapy is limited by the radioresistance of tumor cells, a phenomenon held responsible for the dismal prognosis of the most aggressive brain tumor types. A promising approach to radiosensitization of tumors is the inhibition of cell cycle checkpoint control responsible for cell cycle progression and the maintenance of genomic integrity. Inhibition of the kinases involved in these control mechanisms can abolish cell cycle checkpoints and DNA damage repair and thus increase the sensitivity of tumor cells to radiation and chemotherapy. Here, we discuss preclinical progress in molecular targeting of ATM, ATR, CHK1, CHK2, and WEE1, checkpoint kinases in the treatment of brain tumors, and review current clinical phase I-II trials. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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22 pages, 1366 KiB

Open AccessReview

Role of Fibroblast Growth Factors Receptors (FGFRs) in Brain Tumors, Focus on Astrocytoma and Glioblastoma

by Alessio Ardizzone, Sarah A. Scuderi, Dario Giuffrida, Cristina Colarossi, Caterina Puglisi, Michela Campolo, Salvatore Cuzzocrea, Emanuela Esposito and Irene Paterniti

Cancers 2020, 12(12), 3825; https://doi.org/10.3390/cancers12123825 - 18 Dec 2020

Cited by 35 | Viewed by 7360

Abstract

Despite pharmacological treatments and surgical practice options, the mortality rate of astrocytomas and glioblastomas remains high, thus representing a medical emergency for which it is necessary to find new therapeutic strategies. Fibroblast growth factors (FGFs) act through their associated receptors (FGFRs), a family of tyrosine kinase receptors consisting of four members (FGFR1–4), regulators of tissue development and repair. In particular, FGFRs play an important role in cell proliferation, survival, and migration, as well as angiogenesis, thus their gene alteration is certainly related to the development of the most common diseases, including cancer. FGFRs are subjected to multiple somatic aberrations such as chromosomal amplification of FGFR1; mutations and multiple dysregulations of FGFR2; and mutations, translocations, and significant amplifications of FGFR3 and FGFR4 that correlate to oncogenesis process. Therefore, the in-depth study of these receptor systems could help to understand the etiology of both astrocytoma and glioblastoma so as to achieve notable advances in more effective target therapies. Furthermore, the discovery of FGFR inhibitors revealed how these biological compounds improve the neoplastic condition by demonstrating efficacy and safety. On this basis, this review focuses on the role and involvement of FGFRs in brain tumors such as astrocytoma and glioblastoma. Full article

(This article belongs to the Special Issue Brain Tumors: Molecular and Cell Biology for Target Therapy)

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